Synthesis and biological evaluation of N-substituted 3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic acid derivatives as tubulin polymerization inhibitors

  • Eur J Med Chem. 2018 Jan 1:143:8-20. doi: 10.1016/j.ejmech.2017.08.018.
Jianguo Qi  1 ,  Haiyang Dong  1 ,  Jing Huang  1 ,  Shufeng Zhang  1 ,  Linqiang Niu  1 ,  Yahong Zhang  2 ,  Jianhong Wang  3
Affiliations
  • 1. Key Laboratory of Natural Medicine and Immuno-Engineering of Henan Province, Henan University Jinming Campus, Kaifeng, 475004, Henan, China.
  • 2. Key Laboratory of Natural Medicine and Immuno-Engineering of Henan Province, Henan University Jinming Campus, Kaifeng, 475004, Henan, China. Electronic address: [email protected].
  • 3. Key Laboratory of Natural Medicine and Immuno-Engineering of Henan Province, Henan University Jinming Campus, Kaifeng, 475004, Henan, China. Electronic address: [email protected].
PMID: 29172084 DOI: 10.1016/j.ejmech.2017.08.018
Abstract

A series of novel N-substituted 3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxy- lic acid derivatives were synthesized and evaluated for their biological activities. Among all synthesized target compounds, 13d exhibited the most potent antiproliferative activity against HeLa, SMMC-7721, K562 cell line (IC50 = 0.126 μM, 0.071 μM, 0.164 μM, respectively). Furthermore, compound 13d inhibited tubulin polymerization (IC50 = 3.97 μM), arrested cell cycle at the G2/M phase and induced Apoptosis. The binding mode at the colchicine binding site was also probed. These studies provided a new molecular scaffold for the further development of antitumor agents that target tubulin.

Keywords
3-Oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic acid derivatives; Antiproliferative; Cell apoptosis; Cell cycle analysis; Tubulin polymerization inhibitors.